DESCRIPTION: Relapse is one of the most serious challenges facing successful treatment of cocaine addiction. Although the neurobiological basis of relapse is still poorly understood, growing evidence points to incidental re-exposure to cocaine (drug priming), environmental stimuli associated with previous cocaine use (drug cues), and stressful life events as key factors triggering craving and relapse in people. A comprehensive understanding of these relapse triggers is likely to lead to more effective treatment strategies. Research proposed in this application will make use of a novel nonhuman primate model developed during the previous project period to investigate neurobiological mechanisms underlying relapse to cocaine-seeking behavior. Specific Aim 1 will use selective dopamine receptor agonist and antagonists in conjunction with quantitative analytical techniques (pA2, isobolographic analysis) to delineate the roles of D1-like and D2-like receptor mechanisms in relapse to cocaine-seeking behavior. These studies will determine the degree and specificity with which selective D 1/5, D2, D3 and D4 receptor ligands mimic and/or modulate the reinstatement of drug seeking induced by cocaine priming and a cocaine-paired stimulus. Specific Aim 2 will use a complementary strategy to investigate the role of other monoaminergic (NE, 5-HT) as well as glutamatergic (NMDA, AMPA) mechanisms in relapse cocaine-seeking behavior. Specific Aim 3 will build on recent findings to develop a nonhuman primate model of relapse induced by social stress, to determine the relationship between behavioral and physiological markers of stress and relapse to cocaine-seeking behavior, and to investigate the role of corticotropin-releasing factor (CRF) and the hypothalamic-pituitary-adrenal (HPA) axis in stress-induced relapse. Overall, the proposed research will provide fundamental information about the neurobiological basis of relapse to cocaine-seeking behavior and will facilitate development of effective strategies for relapse prevention.